Standard Operating Procedure:
SOP Number:
Management of Deviations,
Breaches and Urgent Safety
Measures
UoA-NHSG-SOP-045
Author:
Version No:
Date:
1
27th March 2015
(Patricia Burns, Research Governance Manager, University of Aberdeen)
Approved by:
Date:
27th March 2015
Date:
27th March 2015
(Professor Julie Brittenden, R&D Director, NHS Grampian)
Approved by:
(Prof David Reid, Head of School of Medicine & Dentistry, University of Aberdeen)
Issue Date:
1-4-15
Date Effective:
15-4-15
Review Due Date: 1-4-18
Document History:
Version
No.
Description of Changes
Date Approved
1
New SOP (replacing UoA-NHSG-SOP-015 ‘Handling
breaches of the trial protocol and/or GCP in interventional
research projects’).
1-4-15
This SOP will be reviewed at least every 3 years from initial and subsequent issue dates.
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1.
PURPOSE/INTRODUCTION
1.1
The purpose of this Standard Operating Procedure (SOP) is to describe the
procedure for identifying and managing Deviations, Breaches (Serious and NonSerious) and Urgent Safety Measures, identified as a non-conformance with an
approved research protocol, and/or the principles of Good Clinical Practice (GCP).
1.2
This SOP complies with the Scottish Executive Health Department’s Research
Governance framework for Health and Community Care (current version) and the
requirements of the Medicine for Human Use (Clinical Trials) Regulations 2004 and
2006 (the UK Clinical Trial Regulations).
2.
SCOPE
2.1
This SOP applies to all researchers and Sponsor staff participating in all studies
sponsored or co-sponsored by University of Aberdeen (UoA) or NHS Grampian
(NHSG). Interventional research projects include Clinical Trials of Investigational
Medicinal Projects (CTIMP) falling under the Medicines for Human use (Clinical
Trials) Regulations 2004 and related amendments, and other interventional studies
(e.g. surgical studies, device studies, non CTIMP drug studies and any other projects
deemed to be ‘interventional’ by the Sponsor).
2.2
UoA-NHSG SOPs may also be used by staff from other NHS areas, or
organisations, with prior agreement.
2.3
For research projects which are sponsored externally to the UoA or NHSG, local
researchers and support staff should refer to the respective Sponsor’s procedure
and any timelines for handling Breaches and Urgent Safety Measures.
3.
RELATED DOCUMENTATION
UoA-NHSG-SOP-003
UoA-NHSG-SOP-006
UoA-NHSG-SOP-012
UoA-NHSG-SOP-014
UoA-NHSG-SOP-016
UoA-NHSG-SOP-020
UoA-NHSG-TMP-067
4.
Writing a Protocol for CTIMPs to GCP
Study Start Up
Data Management for Clinical Trials
Recording, Managing and Reporting AEs, SAEs & SUSARs
Managing and Maintaining a Training Record
Study Closure Including Procedure for the Sudden Closure
or Suspension of a Trial
Breach Report form
REFERENCES
 Scottish Executive Health Department Research Governance Framework for
Health and Community Care 2006.
 UK Medicines for Human Use (Clinical Trials) Regulations 2004.
 National Research Ethics Service/Health Research Authority website.
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 Medicine and Healthcare Products Regulatory Agency website (MHRA).
Current versions of these documents can be accessed via the Research
Governance Website:
http://www.abdn.ac.uk/medical/researchgovernance/clinicalresearch
ICH E9 Guideline Statistical Principles For Clinical Trials Website:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/
Step4/E9_Guideline.pdf
It is assumed that by referencing the principle regulations, all subsequent
amendments made to the principle regulations are included in this citation
4.1
ABBREVIATIONS AND DEFINITIONS
AE
CAPA
CI
CRF
CSOG
CTIMP
GCP
MHRA
NHSG
PI
REC
SAE
SUSAR
TMF
UoA
Adverse Event
Corrective and Preventive Action
Chief Investigator
Case Report Form
Clinical Studies Oversight Group
Clinical Trials of Investigational Medicinal Product
Good Clinical Practice (ICH)
Medicines and Healthcare Products Regulatory Agency
NHS Grampian
Principal Investigator
Research Ethics Committee
Serious Adverse Event
Suspected Unexpected Serious Adverse Reaction
Trial/Project Master File
University of Aberdeen
5.
DEFINITION OF A DEVIATION, BREACH (SERIOUS AND NON-SERIOUS) AND
URGENT SAFETY MEASURES
5.1
It is the CI’s responsibility to ensure that all researchers adhere to the approved
protocol, Sponsor SOPs and GCP at all times. The only exception is when a
deviation is required for the safety of a participant (see Management and Reporting
of Urgent Safety Measures at 12).
5.2
A Breach is a departure from the approved protocol, research project
documentation, SOPs or any other information relating to the conduct of the trial.
A Non-Serious Breach may be considered a ‘minor non-conformance’ or ‘violation’
and has no impact on a participants’ safety or wellbeing, and/or the scientific integrity
of the research. No substantial amendment is required to the approved protocol, trial
documentation or trial SOPs.
Examples of A Non-Serious Breach include:
A study visit out with a defined schedule;
Boxes on the consent form ticked rather than initialled;
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Misplaced consent form (completed but mis-filed).
A Non-Serious Breach may be upgraded, upon review, to a Serious Breach.
It should be noted that repeated Non-Serious Breaches which become systematic, or
impact multiple participants, may be regarded as a Serious Breach and should be
reported as such.
5.3
A Serious Breach is defined as a Breach which is likely to affect, or have the
potential to affect, to a significant degree:
 The safety, physical or mental integrity of the research participants; and/or
 The scientific value of the research.
This definition is adapted from the Medicines for Human Use (Clinical Trial)
Regulations 2004.
5.4
A Deviation is a minor deviation from an SOP or a planned event. Examples
include:
An SOP being used beyond its review date;
An audit or monitoring visit taking place outside of schedule.
A Deviation may be upgraded, upon review, to a Non-Serious Breach or Breach.
5.5
An Urgent Safety Measure occurs when a research participant is identified as being
at risk of harm in relation to their involvement in a research project and urgent action,
which deviates from the approved protocol, is required to manage the event and
protect the participant(s). An Urgent Safety Measure does not have prior approval
from REC, MHRA or the Sponsor.
5.6
Urgent Safety Measures must be reported to REC, MHRA and Sponsor immediately
after they are implemented.
5.7
Deviations, Breaches and Urgent Safety Measures shall be recorded in such a way
that their impact on the research project can be independently assessed during the
conduct, reconstruction and reporting of the trial. Full details shall include any
Corrective and Preventive Actions (CAPA) identified.
5.8
Relationship between a Deviation, Non-Serious Breach and Serious Breach.
Deviation
Non-Serious Breach
Serious Breach
A Deviation shall be reviewed by the Research Governance Team and/or QA and
may be upgraded to a Non-Serious Breach.
A Non-Serious Breach shall be reviewed by Research Governance Team and/or QA
and may be upgraded to a Serious Breach, or downgraded to a Deviation.
A Serious Breach shall be reviewed by Research Governance Team and/or QA and
may be downgraded to a Non-Serious Breach, or a Deviation.
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6
PROCEDURE
6.1
A Deviation or Breach may be identified and reported by Sponsor or by CI/research
team (to Sponsor). The CI, as Sponsor delegate, must ensure that potentially
Serious Breaches of the research protocol and/or the principles of GCP are reported
to the Sponsor within 24 hours of being identified. In a multi-site project, if such a
breach has occurred at a remote investigational site, the PI shall report the Breach to
the CI, and the CI to Sponsor within 24 hours.
6.2
The Sponsor is responsible for reporting Serious Breaches in CTIMPs and device
studies to the MHRA within 7 calendar days of the Breach being notified to
Sponsor.
6.3
For all research projects, the CI is responsible for reporting Serious Breaches to the
relevant Research Ethics Committee (REC) within 7 calendar days of the Breach
being confirmed as serious.
6.4
Deviations and Breaches shall be recorded on the Log of Deviations, Breaches and
Urgent Safety Measures (Appendix 1) and Breaches reported using the Breach
Report form (UoA-NHSG-TMP-067), unless previously agreed with Sponsor.
The report shall include:
 An overview of the incident and its cause;
 Detail of Corrective and Preventive Action (CAPA);
 An assessment of the likelihood of a recurrence;
 An impact assessment on any work performed prior to the event, which may
be compromised;
 Outline of any changes which may be required to the protocol;
 Likely timeline for CAPA and amendment approval (if applicable).
6.5
The CI shall make an initial assessment as to whether a Breach is Non-Serious or a
Serious Breach (as defined above). The CI shall contact the Research Governance
Manager who shall review and make a final assessment on seriousness, in liaison
with the Quality Assurance Manager.
If deemed a Serious Breach the Research Governance Manager shall set up a
Breach Assessment Team to discuss the Breach and report to MHRA within 7
calendar days of the Breach being notified to Sponsor.
6.6
For all breaches, the completed Breach Report Form and updated Breach Report
Log should be forwarded to the Research Governance Team within 24 hours of the
CI becoming aware of the Breach to pharmaco@abdn.ac.uk. The Research
Governance Team shall acknowledge receipt within 24 hours.
6.7
The CI of the research project is responsible for ensuring mechanisms are in place
to monitor research activity and identify any deviations from the study protocol or
GCP. The CI may share this responsibility with other members of the research team,
or a steering committee. Any such arrangements which are in place should be
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documented in the Investigator Trial Master File.
6.8
A log of Deviations, Breaches and Urgent Safety Measures (Appendix 1) must be
available in the TMF and completed as necessary by the CI. The CI may delegate
responsibility for completing the log to named persons on the study delegation log.
6.9
A Non-Serious Breach (i.e. not judged to impact participant safety and/or scientific
integrity of the research project) should be noted in the TMF and/or Case Report
Form (CRF) and source documents, explaining any actions taken and their
justification.
6.10
Actions taken to investigate a Breach may include an audit of the affected area, an
impact assessment to establish work which is/has been affected, and identifying
CAPA and an appropriate CAPA plan. If the Sponsor identifies a Breach during
routine audit/monitoring, they shall agree CAPA and may request an impact
assessment to establish work which is/has been compromised.
6.11
If a Breach is deemed Serious the Sponsor may suspend the project until all
necessary CAPA have been implemented.
7
SPONSOR ASSESSMENT AND FURTHER INVESTIGATION OF A BREACH
7.1
Where required, the Research Governance Manager, in liaison with the Quality
Assurance Manager, will facilitate a systematic evaluation of the issue with a Breach
Assessment Team comprising; the CI or PI, the lead physicians for the Sponsor(s),
and key members of the research team (e.g. Trial Manager), as appropriate. The
Breach Assessment Team will involve experts from within the Sponsor organisations
or external parties as required. In some cases the Breach Assessment Team may
request further investigation is carried out before an assessment can be made.
The assessment made by the Breach Assessment Team will:
Confirm whether the Breach comprises a Serious Breach or not,
Identify which section of GCP or the approved protocol has been breached,
Identify how the Breach impacts on trial participants and/or the scientific
integrity of the research.
7.2
The Breach Assessment Team will make a judgement whether to implement any
Urgent Safety Measures, such as stopping the research project or specific aspects of
the project immediately, pending any further investigation as necessary (see UoANHSG-SOP-020 ‘Study Closure Including Procedure for the Sudden Closure or
Suspension of a Trial’). The CI retains the right to implement any urgent safety
requirements before the Breach Assessment Team conducts its assessment.
7.3
The Breach Assessment Team will work with the CI to identify the extent of the
Breach and make a CAPA plan. The Breach Assessment Team will agree who
needs to be notified of the Breach and any follow up actions required. In addition, all
records of assessments of potential Serious Breaches will be retained, even if these
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breaches were not deemed serious by the assessment team.
8
NOTIFICATION OF SERIOUS BREACH TO THE RELAVANT PARTIES
8.1
For all Interventional Studies the CI will inform the Project Management Group and,
where applicable, the relevant Trial Steering Committee(s) and/or Data Monitoring
Committee(s) of the Serious Breach. In certain situations only limited details of the
Breach may be reported to the committees in order to maintain trial blinding.
8.2
The Research governance Manager (RGM) shall report all Interventional Study
Breaches to the Clinical Studies Oversight Group (CSOG) at its next meeting or an
extraordinary meeting called for this purpose.
8.3
The RGM will notify the MHRA of a serious breach using the Notification of Serious
Breach template provided within the MHRA Serious Breach guidance (current
version available on the MHRA website)
http://www.gov.uk/good-clinical-practice-for-clinical-trials#report-a-serious-breach
Copies of all Serious Breach Notifications will be filed in the relevant Trial Master File
(TMF) and the Sponsor files.
8.4
For all other Interventional Studies the CI will forward the Breach Report form (UoANHSG-TMP-66) and the Notification of Serious Breach template (MHRA) to the REC
that provided the favourable opinion for the study, and the local NHS R&D
departments for the sites where the Serious Breach occurred, copying in
pharmaco@abdn.ac.uk.
9
CTIMPS: PROVIDING FOLLOW UP REPORTS TO THE RELEVANT PARTIES
9.1
The Research Governance Manager is responsible for follow up notifications to
relevant authorities.
9.2
The Sponsor will keep the Breach under review in order to close out the agreed
CAPA and identify any additional information and forward follow up reports to the
MHRA, REC and local NHS R&D office(s), until the Breach is formally closed by
MHRA.
9.3
The MHRA may request additional information (e.g. current protocol, standard
operating procedures, corrective action plan). The CI/PI or delegated individual
should provide all requested documents to the RGM, to be forwarded on to MHRA
on behalf of the Sponsor.
10
PLANNING AND IMPLEMENTING CORRECTIVE AND PREVENTIVE ACTION
10.1
The Breach Assessment Team will liaise with the CI/PI to implement a CAPA plan to
address the Breach.
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10.2
Dependent on the initial assessment of the extent and impact of the Serious Breach,
the Breach Assessment Team may request that an audit is undertaken of the
research project and/or associated programme of work and or additional research
projects which may be impacted, including an assessment of management systems
and procedures.
11
NON-SERIOUS BREACH
11.1
Non-Serious Breaches shall be referred by the Research Governance Manager to
the Clinical Trials Facilitation Group (CTFG) for assessment and confirmation. The
Research Governance Manager shall notify the CI of this outcome.
The CTFG may, upon review, upgrade a Non-Serious Breach to a Serious Breach.
12
MANAGEMENT AND REPORTING OF URGENT SAFETY MEASURES
12.1
Under the Medicines for Human Use (Clinical Trials) Regulations 2004 the Sponsor,
CI or PI may implement Urgent Safety Measures (USM) to protect trial participants
from immediate harm. Where possible the CI or PI should decide on the appropriate
action after discussion with a Co-Investigator and document this in the Investigator
TMF or Site File.
12.2
Any Urgent Safety Measure (USM) relating to an Investigational Medicinal Product
project must be notified to REC and MHRA within three days of the action being
taken. The Sponsor and the QA Manager should be notified immediately, and
before the MHRA and REC, to advise on the procedure and ensure they are aware
of the details (should the REC or MHRA contact them directly for further information).
The notification should describe the event, the measures taken and justification for
the measures taken. The MHRA can be contacted via email at
clinicaltrialshelpline@mhra.gsi.gov.uk and stating ‘Urgent Safety Measures’ in the
subject title.
The REC should be notified in writing and the Sponsor and QA Manager copied into
communications.
All communications should be copied to the TMF.
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Appendix - 1 Log of Deviations, Breaches and Urgent Safety Measures
STUDY TITLE:
EUDRACT NUMBER:
CI:
SITE NAME AND ADDRESS:
DATE
INCIDENT
ADDED TO
LOG
INCIDENT
PARTICIPANT
DATE
NUMBER
DEVIATION, NONSERIOUS BREACH,
SERIOUS BREACH
OR URGENT
SAFETY MEASURE
(USM)
SITE CORRECTIVE ACTION
SITE PREVENTIVE ACTION
DATE REPORTED TO
SPONSOR
URGENT SAFETY
MEASURE
REPORTED TO
MHRA, REC,
R&D QA
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